A significant health problem for patients receiving chronic opioids for the relief of severe pain is the development of tolerance to the opioid's actions so that escalating doses of the opioid are required to maintain corresponding levels of analgesia. However, some opioids produce more pronounced tolerance than others and this difference has been suggested to be due to the opioid's ability to activate the receptor, or intrinsic efficacy. One strategy to clinically hinder tolerance might be to give opioids with varying efficacies in different sequences of chronic opioid treatment. Preclinical studies of repeated opioid treatment with various mu agonists may be useful in predicting the role of agonist intrinsic efficacy in tolerance and cross-tolerance development. A rat tail- withdrawal assay will be employed as a measure of antinociception. Briefly, the rats will be loosely restrained in rodent restrainers and 5-10 cm of the tail will be placed into 40 degrees and 55 degrees C water. The latency to tail-withdrawal is measured as the dependent variable and a 15 sec cut-off latency is imposed. Using this assay, the proposed experiments will examine the pattern of tolerance development to the antinociceptive effects of etorphine, etonitazene, morphine, buprenorphine, and GPA 1657 when subjects are treated chronically with etonitazene, morphine, buprenorphine, and GPA 1657, respectively. The pattern of tolerance development will be compared across agonists to determine if the degree of tolerance varies with relative intrinsic efficacy. Receptor theory would predict that the greatest degree of tolerance will be observed for the purported lower efficacy agonists, buprenorphine and GPA 1657, since these agonists typically require a greater fraction of the receptor population to produce a maximum effect. A smaller degree of tolerance may be observed for the purported higher efficacy agonists etorphine, etonitazene, and morphine since these agonists typically require a smaller fraction of the receptor population to produce a maximum effect. All five agonists will be studied in cross-tolerance experiments with the other four agonists in order to assess the possibility that chronic treatment with a lower efficacy agonist, such as buprenorphine or GPA 1657, will produce a greater degree of tolerance to all agonists than will chronic treatment with a higher efficacy agonist such as morphine, etorphine, or etonitazene. Experiments will study the effects of increasing maintenance doses of all five agonists on patterns of tolerance and cross-tolerance in order to characterize the relationship of agonist intrinsic efficacy to maintenance dose. Experiments will also characterize the pattern of recover for high efficacy agonists such as morphine, etorphine, and etonitazene and for low efficacy agonists such as buprenorphine and CPA 1657.